The goal of this project is the synthesis of new inhibitors of the enzyme myristoyl-CoA: protein N-myristoyltransferase (NMT). This enzyme catalyzes the covalent modification of specific proteins by acylating the amino group of N-terminal glycines with myristoyl-CoA. Biomedically important proteins which are myristoylated include oncoproteins such as p6O src and the gag polypeptide of HIV and other retroviruses. The goal of this project is to design and synthesize inhibitors of protein myristoylation that are active in vivo for testing as antiretroviral agents. More than 35 analogs of the substrate, myristoyl-Co-A, or of the myristoylated peptide product have been synthesized. These include compounds designed to be either competitive or irreversible inhibitors of NMT. All have been tested in an in vitro NMT assay developed within this project. The regions of the substrates and products that are necessary for high-affinity binding to NMT are being identified and incorporated into future syntheses. One synthetic compound has shown activity in the renal cancer panel of the NCI In Vitro Primary Antitumor Screen. It has been selected by the NCI Biological Evaluation Committee for further testing in mice.